Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease

Abstract

Summary:We report a patient with pre-existing end-stage renal disease (ESRD) who underwent successful matched related donor allogeneic bone marrow transplantation for AML in second complete remission (CR2) using conditioning with high-dose cyclophosphamide (CY, 60 mg/kg/day ؋ 2) and TBI (165 cGy twice daily ؋ 4 days). The timing of hemodialysis after high-dose CY was extrapolated from available data on the pharmacokinetics of high-dose CY and hemodialysis clearance of conventional dose CY and its metabolites. Pharmacokinetic analyses indicated that the elimination of highdose CY and its alkylating metabolites is impaired in ESRD but is cleared with hemodialysis. The patient's early post-transplant course was uncomplicated, and WBC and platelet engraftment occurred by day ؉22. Bone marrow examination on day ؉25 showed trilineage engraftment with no AML; cytogenetics showed 100% donor karyotype. The patient remains in remission with 100% donor karyotype at 3 years post transplant. Clinical results indicate that the administration of high-dose CY is feasible with hemodialysis support for patients with ESRD. Keywords: allogeneic BMT; renal disease; cyclophosphamide; AML; pharmacokinetics; hemodialysis High-dose chemotherapy with BMT is considered to be contraindicated in patients with severe renal dysfunction since it is often assumed that the pharmacokinetics and/or pharmacodynamics of high-dose chemotherapy are significantly altered. High-dose cyclophosphamide (CY) is a common component of preparative regimens. The effect of renal dysfunction on the pharmacokinetics of high-dose CY is not known although pharmacokinetic models suggest that Correspondence: Dr JJ Perry, Section of Hematology/Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, USA 27157 Received 9 July 1998; accepted 12 November 1998 clearance of two important CY metabolites, 4-OH CY and aldophosphamide, may be reduced if severe renal impairment is present.1 The pharmacokinetics of conventionaldose CY and its alkylating metabolites are altered in patients with renal insufficiency.2,3 However, the toxicity profile has not been reported to be different from patients with normal renal function 4 leading some authors to suggest that conventional doses of CY do not require modification in patients with renal dysfunction. 5 In this report, we describe the clinical BMT course of a patient with endstage renal disease (ESRD) (on chronic hemodialysis) and AML in CR2 who received high-dose CY. The pharmacokinetics of high-dose CY and CY-alkylating metabolites are also presented. Case reportA 42-year-old male was diagnosed with AML (subtype FAB-M2) in January 1994. He achieved CR after treatment with daunorubicin 45 mg/m 2 i.v. × 3 days and cytarabine 100 mg/m 2 /day by continuous i.v. infusion (CIVI) ϫ 7 days. He was given four courses of post-remission therapy using daunorubicin 45 mg/m 2 i.v. ϫ 2 days and cytarabine 100 mg/m 2 /day CIVI ϫ 5 days, completed in July 1994. ...

How I treat acute myeloid leukemia presenting with preexisting comorbidities

“…Allogeneic transplantation in patients on chronic dialysis has been reported. 47,48 Ordinarily, we do not consider it except in rare cases of a young highly motivated individual who has a very poor-prognosis genotype.…”

Allogeneic hematopoietic cell transplant for patients with end stage renal disease requiring dialysis – a single institution experience

“…In addition, timing of the first dialysis after cyclophosphamide has been variable ranging from 6 to 14 hours. 13–14 In our patients, the lower doses (14.5 mg/kg/day on each of 2 successive days) of cyclophosphamide in the conditioning regimen were not changed; however, the higher dose (50 mg/kg) cyclophosphamide scheduled for day 3 after transplant used as GVHD prophylaxis was reduced by 25%. In both instances, the drug was given after dialysis.…”

Management of hematological malignancies in patients affected by renal failure

“…Therefore, documented experiences in this setting remain extremely limited. Indeed, to the best of our knowledge, only four case reports have been published, demonstrating the feasibility of allogenic HSCT in carefully selected patients [114][115][116][117]. Reduced-intensity conditioning allogeneic HSCT has been proposed as an alternative transplantation option to reduce HSCT-related toxicity.…”